Growth of the adult kidney may occur by hypertrophy (e.g. following reduction of renal mass) or hyperplasia (e.g. following acute tubular necrosis). The factors which control these different patterns are unknown. Furthermore, the existence of a kidney-specific growth factor has never been established with certainty. In the proposed studies we will examine the hypothesis that angiotensin II, which is generated locally within the kidney, is a growth factor for renal proximal tubular (PT) cells, but rather than acting like most growth factors to stimulate cell proliferation, it causes hypertrophy of the cell. We further postulate that the interactions of angiotensin II with two other molecules produced by the kidney i.e. epidermal growth factor (EGF) and growth inhibitor/transforming growth factor (GI/TGFBeta) determine whether hypertrophy or hyperplasia occur. According to this approach, moderate elevation of the local angiotensin II concentration would cause hypertrophy whereas more exaggerated increments would potentiate the effects of non-mitogenic concentrations of EGF to cause hyperplasia. These effects will be studied in vitro on primary cultures of PT cells as will the role of GI/TGFBeta production in determining the pattern of the growth response. The mechanism of action of angiotensin II will be studied by examining its effects on membrane phosphoinositide turnover, prostaglandin E2 synthesis and Na/H antiport. The causal role of the latter two processes in hypertrophy will be evaluated by selective blockade during prolonged exposure to angiotensin II.